Obesity and type 2 diabetes (2DM) affect millions of people and are the cause of major health problems in the United States. Both conditions have a long array of life threatening complications, including cardiovascular diseases. Despite intense research, the primary defects causing obesity and/or 2DM are still largely unknown. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic physiology, neuroendocrinology and behavior of body energy and glucose homeostasis is needed. The hypothalamus and metabolic-sensor proteins exert important functions on energy and glucose balance. Here, by employing neuron-specific, Cre/loxP-mediated manipulations, unique animal models in which SIRT1 (a metabolic-sensor protein) is either overexpressed or deleted only in restricted hypothalamic neurons will be generated. These mice will be subjected to several phenotypic tests to determine whether SIRT1 in hypothalamic neurons is required for normal body weight and glucose homeostasis. Results from these studies are expected to increase our understanding of the molecular mechanisms and neurocircuits that underlie coordinated control of energy and glucose homeostasis. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes affect millions of people and are the cause of major health problems in the United States. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic mechanisms of body energy and glucose homeostasis is needed. The study proposed here is aimed at identifying these mechanisms (proteins and neurons) that in concert govern body weight and glucose balance.